JPS63295581A - Benzofuro(3,2-c)quinoline derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I {R<1> is 2-10C alkyl or substituted 1-6C alkyl; R<2> is H, OH or -OR<3> [R<3> is (substituted) 1-10C alkyl]}. EXAMPLE:3-Isopropoxy-5H-benzofuro[3,2-c]quinolin-6-one. USE:Useful as a remedy for osteoporosis having inhibitory action on bone resorption and promoting action on osteogenesis. PREPARATION:For example, a compound expressed by formula II (R<3> is H or OH) is reacted with a compound expressed by the formula R<1>-X (X is acid residue) in the presence of a basic substance in an inert organic solvent.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention provides a novel benzofuro (3,2
-C:] This relates to a quinoline derivative.

More specifically, the object of the present invention is to provide a compound of the general formula (I) which has a bone resorption inhibiting effect and an osteogenesis promoting effect and is useful as a therapeutic agent for osteoporosis. A straight-chain or branched alkyl group, or a straight-chain or branched alkyl group having 1 to 6 carbon atoms and having at least one hydroxyl group, carboxy group, carbamoyl group, or alkoxycarbonyl group as a substituent. R2 is a hydrogen atom,
hydroxyl group or the formula -OR' (R3 in the formula is a straight or branched alkyl group having 1 to 10 carbon atoms, which may have a hydroxyl group, a carboxy group, a carbamoyl group, or an alkoxycarbonyl group as a substituent); benzofuro I"3.2-C)
An object of the present invention is to provide quinoline derivatives.

[Conventional technology]

Osteoporosis is a pathological condition in which bone mass is decreased without any change in the chemical composition of bones, and its physiological characteristic is a decrease in protein, calcium, and phosphorus in bones.

Osteoporosis increases with age and usually affects the spinal cord, causing back pain and shortening of height. In particularly advanced cases, long bones are also affected, sometimes resulting in fractures.

It is said that most of the causes of femur fractures seen in the elderly are due to senile osteoporosis.

There are various causes of this osteoporosis, including endocrine and nutritional disorders, but vitamin D preparations, calcium preparations, calcitonin preparations, phosphorus preparations, etc. that have been used as therapeutic agents for osteoporosis have not been targeted. Since the effects are limited and the effects are uncertain, there is a strong desire to develop formulations with more reliable efficacy.

In recent years, a certain type of drug with a completely different chemical structure from the above-mentioned preparations has been developed.
It has been reported that -phenyl-4H-1-benzopyran-4-one derivatives have a bone resorption inhibitory effect and are useful as therapeutic agents for osteoporosis (Japanese Patent Publication No. 13391/1983).
JP-A-60-48924, JP-A No. 60-54379, JP-A No. 60-132917, JP-A No. 60-132976)
.

As the benzofuro[3,2-C]quinoline derivatives of the present invention, compounds represented by the formula or the formula [pretinone
The Chemical Society on Japan (Bu
ll, Chem, Soc, Jpn, ) 53 volumes,
Pages 1057-1060, 1980; Journal on Heterocyclic Chemistry (J, )l
eterocyclicChem,) Volume 16, 487
~491 pages, 1979; Volume 21, 737-73
9 pages, 1984].

However, all of these were synthesized for synthetic interest or to confirm chemical reactivity, and there is no possibility that they may have mutagenic, carcinogenic, or anticancer effects in terms of pharmacological activity. It is only shown, and nothing is written about its effect. Furthermore, it has not been reported at all that benzofuro[3,2-C)quinoline derivatives such as those of the present invention exhibit a bone resorption inhibitory effect and are useful as therapeutic agents for osteoporosis.

[Problem that the invention seeks to solve]

3-phenyl-48-1 disclosed in said patent application
-Benzopyran-4-one derivatives have a weak bone resorption inhibitory effect and are by no means satisfactory as therapeutic agents for osteoporosis. Therefore, the present inventors conducted intensive studies to find compounds with stronger bone resorption inhibitory effects, and found that certain benzofuro C3,2CJ quinoline derivatives or their pharmacologically acceptable salts have strong bone resorption inhibitory effects. It has been found that it has a bone formation-promoting effect and can be an excellent therapeutic agent for osteoporosis.

The present invention is based on these findings.

[Means for solving problems]

Benzofuro C3 represented by the general formula (I) of the present invention,
2-c) Quinoline derivatives or their pharmacologically acceptable salts exhibit strong bone resorption inhibitory and bone formation promoting effects and are useful as highly safe osteoporosis therapeutic agents.

Benzofuro (3,
2-c] A quinoline derivative can be produced as follows. For example, a compound represented by the general formula H (in which R3 is a hydrogen atom or a hydroxyl group) and a compound represented by the general formula (% formula %) (in which X is an acid residue and R1 has the same meaning as above). It can be produced by reacting a compound represented by (with) in an inert organic solvent in the presence of a basic substance.

In this production method, the general formula (
n) The compounds represented by J and general formula (III) are known compounds, with some exceptions, and are available as commercially available products or by methods described in literature, such as Pretin on the Chemical Society Japan (Bull, Ch.
em, Sac, Jpn, ) 53 volumes.

Pages 1057-1060, 1980; Journal on Heterocyclic Chemistry (J, He
tero-cyclic ['hem,) Volume 16, 4
Pages 87-491, 1979-Volume 21, 737-
739, 1984, or similar methods thereof.

Benzofuro (3,
2-c) The quinoline conductor can be converted into a pharmacologically acceptable salt according to a conventional method. For example, a compound in which R2 is a hydroxyl group or a compound in which R1 is an alkyl group having a carboxyl group as a substituent in the benzofuro[3゜2-C]quinoline derivative represented by the general formula (I) of the present invention is similar to this. The sodium salt can be obtained by adding an equivalent amount of hydroxide to an alcohol solution in which IJum is dissolved, heating it, and then concentrating it under reduced pressure.

Benzofuro [3,
2-c) The quinoline derivative can be made into various pharmaceutical preparations according to conventional methods. That is, by mixing with pharmaceutical additives such as excipients, disintegrants, binders, and lubricants as necessary, and preparing according to conventional methods, various preparations such as tablets, powders, capsules, etc. are prepared. be able to.

Benzofuro (3,
2-c) When using a quinoline derivative as a therapeutic agent for osteoporosis, approximately 10 to 1000 mg per day for adults is prepared into an appropriate dosage form, such as tablets, powders, capsules, etc., and administered orally; 1 to 100 mg is administered parenterally in the form of an injection or the like.

Benzofuro [:3] represented by the general formula (I) of the present invention
．． 2-C) Quinoline derivatives or their pharmacologically acceptable salts have shown significant bone resorption inhibitory and bone formation promoting effects at 10-4 to 10-' molar concentrations in in vitro experiments using chicken embryo femurs. shows. Also, 1000-3000
Even when mg/kg was orally administered, there were no deaths and no toxic symptoms were observed, so it is useful as a highly safe osteoporosis treatment.

〔Example〕

In order to further explain the present invention in detail, reference examples and examples are given below. Note that the melting points of the compounds in each Reference Example and Examples are all uncorrected.

Reference Example 1 3-Hydroxy-5H-benzofuro[3,2-c)quinolin-6-one 2.7 g of m-anisidine and 5.32 g of diethyl 2-methoxyphenylmalonate were dissolved in diphenyl ether 20- Attach a cooling pipe and heat at 270-290°C for about 2.
Heated for 5 hours. After cooling, 80 ml of diethyl ether was added, and the precipitated crystals were collected by filtration and washed with diethyl ether to give 5.39 g (90.7%) of 4-hydroxy-7-medoxy-3-(2-methoxyphenyl)-2-quinolone.
) was obtained.

Melting point:>aOO℃ IR (KBr): vco 1620 cm-
'NMR (ds-DMSO) δ: 3.69 (s, 3N), 3.81 (s, 31
(), 6.75-6.79 (m, 2tl), 6.
93-7.13 (m, 3H), 7.29-7.35
(m, 18), 7.76-7.80 (m, IH
).

9, 56 (br-s, IH), 11.18 (s
, IH) Elemental analysis value' (as C + 7 days + 5NO4) 0% 8% N% Calculated value 68.68 5.09 4.71 Actual value 68,79 5.08 4.724-
A mixture of 5 g of hydroxy-7-medoxy-3-(2-methoxyphenyl)-2-quinolone and 50 g of pyridine hydrochloride was heated under reflux at 220-250° C. for 2.5-3 hours. Pour the reaction mixture onto 200-300 g of hot crushed ice,
The precipitated crystals were collected by filtration, washed with water, and recrystallized with alcohol to obtain 1.9 g of 3-hydroxy-5H-benzofuro[3,2-C)quinolin-6-one.

Melting point: >300℃ IR (Br): 1640 cm-'
NMR (d6-0M3 ports) δ: 6.92-7.04 (m, 2N), 7.52
~7.60 (m.

2H), 7.89-8.17 (m, 3H), 10
．． 49 (s.

IH), 11.88 (s, IH) Elemental analysis value' (as C+5HsNO*) 0%
8% N% Calculated value 71,71 3,61 5.58 Actual value 71J7 3.61 5.44 Reference example 2 Instead of using diethyl 2-methoxyphenylmalonate, diethyl 2,4-dimethoxyphenylmalonate or 2. The following compounds were synthesized in the same manner as in Reference Example 1 except that diethyl 5-dimethoxyphenylmalonate was used.

Melting point: >300℃ IR (KBr)' Uca 1640 cm
'NMR (ds-DMSO) δ: 6.77~6.9Hm, 3H), 7.11~
7.12 (m.

IH), 7.78-8.30 (m, 2H), 9.
83 (s.

1)1), 10.22(s, 1)1), 11.6
7(s, 1N) elemental analysis value' (C+5HsNO*
) 0% 8% N% Calculated value 67.42 3.39 5.24 Actual value 67.24 3.41 5J5 melt
Point: >300°C rR (KBr): l'c0 1660. 163
0 cm-'NMR (d, -DMSO) δ: 6.77-6.90 (m, 3H), 7
．． 39-7.85 (m.

3H), 9.46 (s, l1l), 10.
31(s, IH).

11.64 (s, LH) Elemental analysis value' (as C+5HsNO*) 0%
8% N% Calculated value 67.42 3.39 5.24 Actual value 67.71 3.45 5.54 Example 1 3-Hydroxy-5■-BenzofuroC3,2-C] Quinolin-6-one 500m Dissolved in 20% N,N-dimethylformamide, 60% sodium hydride (oil-based)
After adding 100 μl of the mixture and stirring for a while, 0.5 ml of isopropyl iosite was added while cooling with water, and the mixture was stirred overnight at room temperature.

The solvent was distilled off under reduced pressure, and the residue was washed with 5% aqueous sodium hydroxide solution, water and diethyl ether, and recrystallized from ethyl acetate to give 3-impropoxy-58-benzofuro (3,2-C] ] 214 mg of quinolin-6-one was obtained.

Melting point: 278-280°C IR (KBr): 1640 cm-'N
MR (CDC13) δ: 1.34 (d, 6H), 4.69 (quin
t, l1l), 6.94-7.03(m, 2)1
), 7.42-7.51 (m, 2H).

7.99-8.07 (m, 3H), 11.79 (s
, 1ft) Elemental analysis value'(CI'1l) 115N
(as O3) 0% 8% N% Calculated value 73,71 5.15 4.78 Actual value ? 3.56 5,15 4.67 Example 2 The following compound was produced in the same manner as in Example 1 except that 3-chloro-1-propatool or ethyl α-bromopropionate was used instead of isopropyliosito. did.

Melting point: 275-280℃ IR (Br): vco 16.40
cm-'NMR (d, -DMSO) δ: 2.04 (t, 2) 1), 3.71 (q,
2H), 4.26 (t.

2H), 7.08-7.15 (m, 2H), 7.
51-7.63 (m, 2H), 7.92-8.20
(m, 3H), 11.96 (s, 1N) Elemental analysis value: (as C+aH+sNO<) 0%
N% N% Calculated value 69.89 4.89 4.53 Actual value 69.61 4.85 4.433-
(1-ethoxycarbonylethoxy)-5H-pen melting point = 209-212°C IR (KBr): vco 1730.
1655 cm-'NMR (ds-MSO) δ: 1.33 (t, 3H), 1.69 (d, 3
H), 4.30 (q.

2H), 5.15(q, IH), 7.06-7.
10 (m, 2N).

7.57-7.62 (m, 2H), 7.95-8
．． 20 (m.

3H), 12.02 (s, IH) Elemental analysis value = (as C2°H, tNOs) 0%
N% N% Calculated value 68J7 4.88 3.99 Actual value 68.58 4.83 4.12 Example 3 3-(1-ethoxycarbonylethoxy)-58-benzofuro(3,2-c)quinoline-6 -On 200■
was dissolved in 10 ml of ethanol, 20 rne of 10% aqueous sodium hydroxide solution was added, and the mixture was heated on a water bath at 80° C. for about 1 hour.

After cooling, acidification with hydrochloric acid was performed, and the precipitated crystals were collected by filtration, washed with water, and recrystallized from aqueous alcohol to obtain 190 mg of 3-(1-carboxyethoxy)-5-day-benzofuro[3,2-c)quinolin-6-one. I got it.

Melting point: 260-266°C IR (KBr): I'CO1750, 1730,
1640Cm-'NMR (d, -DMSO) δ: 1.69 (d, 3H), 5.05 (q, I
H), 7.04-7.08 (m, 2H), 7.5
4-7.64 (m, 2H), 7.90-7.97 (
m, IH), 8.09-8.23 (m, 2H).

11,99(s, LH), 13.30(br-s,
1) l) Elemental analysis value: (as C, aH + 5NOs) 0% N% N% Calculated value 66.87 4.05 4.33 Actual value 66.55 4.05 4.55 Example 4 3-isopropoxy- 9-hydroxy-5H-bensif 3,9-dihydroxy-5H-bensif O[3,2-C
) 267 ml of quinolin-6-one was dissolved in 20 ml of N,N-dimethylformamide, 80 mg of 60% sodium hydride was added and stirred for a while, then 0.4 d of isopropyl iosite was added and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform and extracted with a 5% aqueous sodium hydroxide solution. The organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the remaining crystals were recrystallized from ethyl acetate-〇-hexane.
,9-diisopropoxy-5H-benzofuro (3,2-
C) 130 mg of quinolin-6-one was obtained.

The IJum extract was acidified with hydrochloric acid, and the precipitated crystals were subjected to silica gel column chromatography (elution solvent: methylene chloride/ether/methanol = 20/20/
1) to obtain 45 mg of 3-inpropoxy-9-hydroxy-58-benzofuro (3,2-c)quinolin-6-one.

3.9-diisopropoxy-5H-benzofuro (3,2
-C] Quinolin-6-one Melting point: 246.5 ~ 250°C IR (KBr
): l'c0 1660 Cfl+-'NMR
(d, -DMSO) δ: 1.43 to 1.47 (m, 12) 1), 4
．． 73-4.90 (m.

2B), 7.04-7.16 (m, 3M), 7.
54-7.55 (m, IH), 7.98-8.
03 (m, 2H), 11.85 (s, 1) 1
) Elemental analysis value' (C218□NO, closed) 6%
6% N% Calculated value 71,78 6.02 3.99 Actual value? 1.52 6.01 4.15 fusion
Point: 260-265℃ IR (KBr): L'l: 0 1660 cm
-'NMR (d6-DMSO)' δ: 1.45 (d, 68), 4.79 (quin
t, 18), 7.01-7.26 (m, 4B),
7.91-8.03 (m, 2H).

10.01 (s, IH), 11.82 (s,
1f () Elemental analysis value' (as CIIHISNO4) 6% 6% N% Calculated value 69,89 4.89 4.53 Actual value 69.62 4.83 4.41 Example 5 3- instead of isopropyl iosito The following compound was produced in the same manner as in Example 4 except that chloro-1-propatol or ethyl α-bromopropionate was used.

Melting point: 225-232°C IR (KBr): vco 1660.1630
cm-'NMR (d, -DMSO) δ: 1.99-2.08 (m, 4) 1), 3.6
7-7.45 (m.

4H), 4.24(t, 2H), 4.265(t
, 2H), 7.05-7.19 (m, 3H),
7.54 (d, IH), 7.91-8.04 (m,
2H), 11.91 (s, IH) elemental analysis value: (C
aJa+NOs) 6% 6% N% Calculated value 65.78 5.52 3.65 Actual value 65.53 5.41 3.59
Point: 263.5 ~ 267℃ IR (KBr):
! /Co 1640 cm-'NMR(ds
-DMSO) δ: 2.03 (t, 2H), 3.71 (q, 2
H), 4.26 (t.

2)1), 7.06～? , 26 (m, 4H), 7
．． 91-8.04 (m, 2) 1), 10.01 (s
, 1) 1), 11.90 (s, IH) elemental analysis value' (as C+@H+5NOs) 6% 6%
N% Calculated value 66.45 4.65 4.31 Actual value 66.16 4.53 4.295H
-Benzofuro(3,2-C]]quinolin-6-one Melting point = 187-194°C IR (KBr): vco 1750.1670
．． 1630 cm-'NMR (d, -DMSO) δ: 1.30 (t, 3H), IJ3 (t, 3N
), 1.68 (d.

6H), 4.24-4.34 (m, 4H), 5.
14 (q.

IH), 5.25 (q, IH), 7.05-7.
51 (m, IH).

8.01-8.07 (m, 2H), 11.98 (s
, IH) Elemental analysis value: (C2S) 125N opening, closed) 6% 6% N% Calculated value 64,23 5.39 3.00 Actual value 63.96 5,36 2.97 [Effect of the invention] This Benzofuro C3,2- represented by the general formula (1) of the invention
c) Quinoline derivatives and their pharmacologically acceptable salts were found to be 1.
It exhibits significant bone resorption inhibiting and bone formation promoting effects at 0-4 to io-' molar concentrations. Also, 1000-3000 mg
/ kg was orally administered, there were no cases of death, and no serious poisoning symptoms were observed.

As described above, the benzofuro I''3.2-C]quinoline derivative represented by the general formula (I) of the present invention is an extremely useful compound as a therapeutic agent for osteoporosis.

Claims (1)

[Claims] General formula▲ Numerical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is a linear or branched alkyl group having 2 to 10 carbon atoms, or at least one hydroxyl group , a straight-chain or branched alkyl group having 1 to 6 carbon atoms and having a carboxy group, a carbamoyl group, or an alkoxycarbonyl group as a substituent, and R^2 is a hydrogen atom, a hydroxyl group, or a formula -OR^3 (in the formula R^3 has 1 to 1 carbon atoms and may have a hydroxyl group, carboxy group, carbamoyl group, or alkoxycarbonyl group as a substituent
0 straight-chain or branched alkyl group) benzofuro[3,2-c]
Quinoline derivative.